A method of going about answering the long-term safety issues. That would be
through the development of what might be called the Pharmacovigilance
Program. It would be all the ways you might potentially go about trying to
follow these over time. If you take a look, these are the current programs
that are to assess long-term safety.
Surveillance of Etanercept Spontaneous Safety Reports
Slide. Pharmacovigilance Program
The first one is Safety in Etanercept in Spontaneous Safety Reports. The way
the FDA put that really was facilitated consumer reports, and what does that
really encompass? Well, it encompasses any of us as practitioners as we fill
out a Med Watch Form. A Med Watch Form is the way that any of us, as
providers, can report an adverse event. The other way that etanercept
Spontaneous Safety Reports can come in, can come in through consumer
facilitated reports through an 800 number, which is 1-800-4-E-N-B-R-E-L.
This is the largest way, and should I say the majority of the way that
adverse events become reporting. Any patient that calls the 800 number for
any reason and describes an adverse event, that adverse event will be
logged, it will be followed up, and then it will be reported to the FDA.
What are the long-term etanercept safety trials? There is a long-term safety
trial of etanercept in the United States. There's also a long-term safety
trial with etanercept in Europe. These are for all of the patients that were
randomized at the double-blind, placebo-controlled studies in the past on
etanercept, whether it be placebo or not. These patients are followed
long-term, as long as they're willing, and those adverse events can be
captured in a systematic way. As well there are safety registers. All
patients in Europe that obtain etanercept should be entered in the safety
database. In the United States, all pediatric patients treated for JRA are
entered into the JRA Safety Registry. And lastly, there's a safety study.
This is one that's been done right now in collaboration, both by the FDA and
with Immunex, looking at what happens with patients that are at the highest
risk of adverse event(s). This study takes 1,000 patients that have
comorbidities. In order to get into this study, you have to have
insulin-dependent diabetes, you have to have COPD or asthma, you have to
have had pneumonia in the last year, or you have to have had at least two
upper respiratory tract infections. If you don't have a significant
comorbidity, you can't get into this double-blind, randomized,
placebo-controlled study. The goal here is to assess do these patients
really, or should I say does etanercept really convey increased risk of side
effects for patients that have comorbidities? I think this is the best way
we're going to answer that question in the short-term and potentially the
long-term.
Slide. Etanercept Post-Approval Experience
Looking at etanercept as a whole, it's been available for clinical use in
the United States since November of 1998, available earlier than that in
clinical trials, and that's where our long-term safety studies come from.
Overall, there have been a total of 80,000 patients in the United States
that are receiving Etanercept, and a total of over 60,000 of exposure. How
is that relevant? Well, I think it's relevant because you can put ([a
perspective]) on the adverse events reporting and changes in labels. Labels
get changed for two reasons. Labels get changed predominantly so they can
inform providers of potential risks, and so that those providers can assess
the risk based on their individual prescribing habits, so they can make
decisions about whether or not a therapy is prudent for an individual
patient. Moreover, those changes in the label are designed to help patients
decide if they believe it's prudent, although most of the time, patients
really have not seen a package insert. So for the most part, it's to inform
providers of the potential benefits and risks of the therapy, and we should
be excited about the fact that labels do get changed over time, because
otherwise, most of us would have no good way of knowing what the potential
ramifications of any therapy are. Now with that, have there in fact been
changes?
Slide. Enbrel Label Update-Hematologic Events
The first one is hematologic events. You notice that there is a label change
that occurred this year and most of you received your doctor letters,
whether you're in Europe or North America. What do the safety report or the
label update mandate? Well, there are rare reports of pancytopenia,
including aplastic anemia, some with a fatal outcome. They were reported in
patients with RA that have been treated with etanercept. The problem is
they've also been treated with a lot of other things. The causal
relationship to etanercept remain unclear. Although no high risk group could
be identified, caution should be exercised in treating with etanercept, and
patients that had a previous history of significant hematologic
abnormalities. Patients should be advised, if they develop signs or symptoms
suggestive of a blood dyscrasia or infection, that they should seek medical
attention, and should those hematologic abnormalities be confirmed,
consideration should be made to discontinue your therapy.
Slide. Reported Hematologic Events
Now from what was just predicated, there have, in fact, been rare reported
cases of pancytopenia in the neighborhood of about 11 cases. In fact, there
have been 4 cases of aplastic anemia. Most of these patients have been
treated with significant drugs in the past. They've all been on many prior
disease modifying drugs. Most of them are on multiple concomitant
medications including methotrexate, azathioprine, cyclophosphamide. There
was no causal relationship associated with any of these patients. Some
patients have been on approximately 4 weeks of therapy. Some had been on
every year therapy with etanercept. There was no change recommended in
laboratory monitoring of these patients, although I think in honesty, it's
prudent that we evaluate the way we measure what white cell count, platelet
and hematocrit in our individual patients, based on our perceived risk for
that individual patient.
Slide. Enbrel Label Update-Neurologic Events
Additional changes as a label update associated with neurological events -
rare cases of central nervous system demyelinating disorders were described
as Spontaneous Adverse Event Reports. The causal relationship to etanercept
remains unclear. While no clinical trials have been performed evaluating
etanercept therapy in patients with multiple sclerosis, other TNF
antagonists administered to patients with multiple sclerosis have been
associated with increases in disease activity, and prescribers should
exercise caution, considering the use of etanercept patients with
preexisting or recent-onset CNS demyelinating disorder. The majority of
animal models have suggested that anti-TNF therapy would be beneficial in
down-modulating multiple sclerosis or preventing relapse in remitting
disease. As it turns out, two patients have been treated with CA2 in 1996.
That was the name previously given to infliximab.. These patients
demonstrated increased evidence of lesions on MRI. Only two patients and no
other patients have been treated with infliximab for multiple sclerosis. The
second study was using lenercept, which is P55 fusion protein. This was done
in patients with multiple sclerosis. These patients had more exacerbations
of potentially greater frequency, as well as greater severity in their
exacerbation for multiple sclerosis, but no substantial and no statistically
significant MRI changes over time. Overall, what do we know about patients
that have been treated with etanercept in demyelinating disease?
Slide. Reported Neurologic Events
We know right now that there have been rare reported cases, CNS events,
associated with demyelinating disease. Overall, we know about four cases of
relapse of multiple sclerosis, so patients with MS who had relapsed while on
etanercept. We know of two cases that have new development of multiple
sclerosis with the treatment of etanercept. We know of a sporadic number of
patients of optic neuritis, as well as myelitis, total approximately 9 cases
by the FDA abstract. Overall, this is based on 60,000 patient-years. I guess
the question is, how often does multiple sclerosis occur as a whole, and how
often do we know whether it occurs in RA? Those are difficult questions.
Overall, we would expect about 130 cases per 100,000 patients of multiple
sclerosis. We might expect relapses to occur about once every 12 to 18
months in patients that have multiple sclerosis. We might expect somewhere
in the neighborhood between 2 and 6 cases in any given year. The question
really is, and this one we don't know, is multiple sclerosis or any other
demyelinating disease occurring at a greater frequency based on the
denominator that we have here than it would or without the use of etanercept
or any other CNS inhibitor? There have been, rare new cases of multiple
sclerosis. The question is, are these, in fact, within the expected range?
Based on the data we have now, I suspect they are, but this is one of the
things we need to follow over time. Right now no causal relationship has
been established, associated with etanercept. In fact, some of these
patients have been on etanercept for a short duration; some of these
patients have been on etanercept for a longer duration. Again, other TNF
antagonists administered to patients with MS have been associated with
exacerbation of that disease. Of course, we had not heard publicly about the
exacerbations of MS with other TNF agents in RA at this point. There are
additional label changes.
Slide. Enbrel Label Update-Infections
Those include the label changes associated with infection. There have been
post-marketing reports of serious infections and sepsis, including
fatalities. They're reported with the use of etanercept. Many of these
serious adverse events have occurred in patients with underlying diseases
that, in addition to their rheumatoid arthritis, could predispose them to
infection. Patients who develop a new infection while undergoing treatment
with etanercept should be monitored closely, and administration of
etanercept should be discontinued in cases of serious infection or sepsis.
Treatment with etanercept should not ([be]) initiated in patients with
active infection, including chronic or localized infection, and physicians
should exercise caution when considering the use of etanercept in patients
with a history of recurring infection or underlying conditions, which might
predispose the patients to infection such as advanced or poorly controlled
diabetes. What has been the underlying cause of a label change there?
Slide. Reported Infections
There have been infrequent reports of serious infection, some with fatal
outcome. The question is, how often is this occurring? Are there associated
risk factors? There certainly seem to be on the surface such as diabetes and
other comorbid illnesses. The largest safety study looking at comorbid
illness with the use of TNF inhibitors is already underway.
Slide. Serious Infections and Infection-Associated Mortality
The rate of reported infections in ([the]) post-approval database, for the
most part, has remained stable within rates reported from other clinical
trials. Well, is that in fact true, and what have been the reported rates in
other clinical trials? This is what was most recently recorded by the Mayo
Clinic looking at population-based statistics from Olmsted County. They are,
in fact, 9.2 serious infections based on 100 patient-years with patients
with RA, and 0.6 infection-associated mortalities per 100 patient-years in
RA patients. How does that correspond with other data? Well, looking at data
from the Aramise database would suggest that there is, in fact, a rate of
infection associated mortality of 0.36, infection-associated mortalities per
100 patient-years, very much consistent with this, although slightly lower,
but still higher than what we're seeing with our active therapies. Prior
articles have suggested infection-associated mortality occurring at this
rate, depending on which study and which population is looked at. What have
we seen as far as etanercept clinical trial data and how does it compare
with both our historical controls and our contemporary controls? Looking at
placebo-controlled studies, this was the rate of serious infections as seen
in the etanercept studies. Infection-associated mortality in the studies was
zero here, zero there, and 0.1 infection-associated mortalities per 100
patient-years. And how does that correspond with the overall post-approval
spontaneous safety reports that have been reported? Well, right now we're
seeing less than one serious infection per 100 patient-years in the
spontaneous safety reports, with a rate of 0.1 infection associated
mortalities per 100 patients years. The rate of mortality associated with
infection in the long-term studies and in open-label, spontaneous or
post-marketing experience, still fall shy, ([of]) what we see in the
literature, as well as our control(s) from clinical study. Now overall, what
is the goal of these post-approval spontaneous safety reports?
Slide. Post-Approval Spontaneous Safety Reports
They are clearly useful for new therapy, and the goal is to derive a
database significantly large enough in size to enable the opportunity to
capture uncommon events. More than that, it enables the ability to
potentially capture or find events that may constitute a safety signal, so
that additional studies can be done, or so that providers and patients can
be warned appropriately. It provides an opportunity to inform the medical
community. As well, it provides an opportunity to adjust what might
otherwise be considered a Pharmacovigilance Program.
Long-Term Etanercept Safety Trials (North America and Europe)
Slide. Pharmacovigilance Program
What we know to date about the long-term Etanercept Safety Trial.
Slide. Methods
It's been performed in adults with longstanding rheumatoid arthritis that
had previously been studied in double-blind, randomized, placebo controls in
North America. The evaluations in these patients occur frequently and
routinely, every 3 to 4 months, and adverse events are collected in a
systematic fashion to enable comparison throughout the database.
Slide. Demographics
What's been seen is for those 1,628 patients, roughly 53 years of age, the
majority of these are women, and the mean duration of disease is
approximately 12 years, substantial duration of disease. The majority of
these patients are on corticosteroids and NSAIDs.
Slide. Duration of Exposure (1336 patient-years)
So far, approximately 500 or so have been in this study for a year, another
400 for 2 years, and then smaller numbers have been studied out for 3 and
for 4 years.
Slide. Discontinuations
What we know is that the discontinuation rates have generally been low, and
they're broken up fairly uniformly between adverse events, lack of efficacy,
and then other logistic reasons such as a refusal or moving out of a
particular study area.
Slide. Infections Associated with Hospitalization/IV Antibiotics
What's been seen as far as infection-associated hospitalization, are you
surviving antibiotics, what might be characteristically classified as class
3 or class 4 adverse events. This rate, for the most part, has remained
stable in patients over the period of 4 years. More than that, there have
been no opportunistic infections reported in this study, no increase in rate
over time, and again 88% of these patients have continued on the etanercept.
Slide. Malignancy
There had been malignancy seen, but they have not occurred at frequency
greater than what would be expected for age- and sex-matched controls from
the Seer database at the NIH. There's no predominance and type of
malignancy. What do we know again about mortality?
Slide. Mortality
Well, one that comes up most commonly is how infrequently is
infection-associated mortality occurring? From the Aramise database, there's
a 20% infection-associated mortality in the contemporary cohort of patients.
What we're seeing from the Olmsted County population-based database in the
Mayo Clinic, which suggests infection-associated mortality of approximately
15%, and what we're seeing with etanercept in the long-term database is
approximately 18%. This falls right smack in the middle of what we see
between the Mayo Clinic and what we see as the long-term outcomes from
Stanford and the Aramise database(s).
Slide. Summary
Overall, we see an adverse event profile in the open label extension study
that is similar to what we see in a placebo-controlled trial. We see that
serious infections can occur but they do not occur at increased frequency
over time, we have not seen opportunistic infection, and malignancies have
occurred at a frequency to what would have been expected for age- and
sex-match(ed) control(s). There's been no cumulative toxicity that's been
evident based on clinical trials or in the long-term post-marketing
surveillance. The rare events have been reported with ([the]) post-approval
database, and they have, in fact, led to label updates. The rates and the
types of adverse events seen in these remain stable, up to 4 years of
treatment in this clinical trial, and a large number of patients with RA
have received substantial benefit from etanercept over time. So it's
important to put this in the appropriate context.

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